Variant classification summary

NM_000546.6:c.840A>C

TP53 · NP_000537.3:p.(Arg280Ser) · NM_000546.6

GRCh37: chr17:7577098 T>G · GRCh38: chr17:7673780 T>G

Gene: TP53 Transcript: NM_000546.6

Final call

Likely Pathogenic

PS3 strong PM2 supporting PP3 moderate

Variant details

Gene

TP53

Transcript

NM_000546.6

Protein

NP_000537.3:p.(Arg280Ser)

gnomAD AF

ClinVar

Likely pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 (Strong): R280S is non-functional in the primary Kato transactivation assay and shows loss of function in the majority of other eligible assays, per the VCEP functional worksheet.

2

PM2 (Supporting): the exact variant is absent from gnomAD v4.1, v2.1, and gnomAD-Canada, below the 0.003% threshold.

3

PP3 (Moderate): the VCEP lookup assigns PP3_moderate for c.840A>C with aGVGD class C65 and BayesDel 0.471465.

4

Combined: PS3 strong (+4) + PM2 supporting (+1) + PP3 moderate (+2) = 7 points maps to Likely Pathogenic under the TP53 VCEP v2.4 point-based framework.

Final determination: Under the TP53 VCEP v2.4 Tavtigian point-based framework, a total of 6-9 points is Likely Pathogenic; the applied criteria total 7 points.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Not met	Not met: missense substitution creates no premature stop codon or splice disruption, and SpliceAI max delta 0.00 predicts no splice impact.	cspec pvs1_variant_assessment spliceai vcep_pvs1_flowchart
PS1	Not met	Not met: no alternate-nucleotide p.Arg280Ser variant with a VCEP-qualified pathogenic assertion was found.	cspec pm5_candidates spliceai PMID:10761706
PS2	Not assessed	Not assessed: no proband phenotype, parental testing, or de novo observation was available.	cspec
PS3	Met	Met (Strong): the VCEP functional worksheet assigns R280S non-functional on Kato data and loss of function in the majority of other eligible assays.	cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet PMID:12826609 PMID:30224644 PMID:29979965
PS4	Not assessed	Not assessed: no germline proband-level phenotype or PS4 point total was available; the two reported Arg280Ser tumors are somatic.	cspec vcep_ps4_points_table PMID:10761706
PM1	Not assessed	Not assessed: codon 280 is not in the VCEP-approved PM1 codon list (175, 245, 248, 249, 273, 282).	cspec PMID:27328919
PM2	Met	Met (Supporting): the exact variant is absent from gnomAD v4.1, v2.1, and gnomAD-Canada, below the 0.003% PM2 threshold.	cspec gnomad_v4 gnomad_v2 gnomad_canada
PM3	N/A	Not applicable: the TP53 VCEP designates PM3 not applicable; Li-Fraumeni syndrome is autosomal dominant, not recessive.	cspec
PM4	N/A	Not applicable: this missense substitution does not change protein length, and the VCEP excludes PM4.	cspec pvs1_variant_assessment
PM5	Not met	Not met: no different missense variant at Arg280 with a VCEP-qualified pathogenic classification was found.	cspec pm5_candidates
PM6	N/A	Not applicable: the TP53 VCEP drops PM6 and uses PS2 exclusively for de novo evidence.	cspec
PP1	Not assessed	Not assessed: no affected-family-member genotypes, pedigree, or meiosis count was available.	cspec
PP2	N/A	Not applicable: designated not applicable by the TP53 VCEP.	cspec
PP3	Met	Met (Moderate): the VCEP lookup assigns PP3_moderate for c.840A>C with aGVGD C65 and BayesDel 0.471465; SpliceAI max delta 0.00.	cspec vcep_pp3_bp4_codes spliceai bayesdel
PP4	Not assessed	Not assessed: no observation with a reported 5-35% VAF, which the VCEP mosaic-variant rule requires, was available.	cspec PMID:10761706
PP5	N/A	Not applicable: the VCEP excludes PP5, and no expert-panel ClinVar submission exists for this variant.	cspec clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v4.1, v2.1, and gnomAD-Canada, so no FAF reaches the >=0.001 threshold.	cspec gnomad_v4 gnomad_v2 gnomad_canada
BS1	Not met	Not met: the variant is absent from population databases, so no FAF falls in the BS1 interval (>=0.0003 to <0.001).	cspec gnomad_v4 gnomad_v2 gnomad_canada
BS2	Not assessed	Not assessed: no carrier-level observations, ages, or cancer histories were available.	cspec
BS3	Not met	Not met: the variant's assays show non-functional/loss of function, the opposite of the functional results BS3 requires.	cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet
BS4	Not assessed	Not assessed: no pedigree or non-segregation observations in affected family members were available.	cspec
BP1	N/A	Not applicable: designated not applicable by the TP53 VCEP.	cspec
BP2	N/A	Not applicable: designated not applicable by the TP53 VCEP regardless of phase observations.	cspec
BP3	N/A	Not applicable: this missense substitution is not an in-frame indel, so the repeat-region rule does not apply.	cspec pvs1_variant_assessment
BP4	Not met	Not met: the VCEP assigns PP3_moderate for this exact variant, and BayesDel 0.471465 is outside the BP4 score ranges.	cspec vcep_pp3_bp4_codes spliceai bayesdel
BP5	N/A	Not applicable: designated not applicable by the TP53 VCEP.	cspec
BP6	N/A	Not applicable: the VCEP excludes BP6, and no benign/likely-benign expert-panel assertion exists.	cspec clinvar
BP7	N/A	Not applicable: BP7 applies to synonymous or intronic variants; this is a missense substitution.	cspec

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.